Follistatin-Like Proteins: Structure, Functions and Biomedical Importance

Abstract

Main forms of cellular signal transmission are known to be autocrine and paracrine signaling. Several cells secrete messengers called autocrine or paracrine agents that can bind the corresponding receptors on the surface of the cells themselves or their microenvironment. Follistatin and follistatin-like proteins can be called one of the most important bifunctional messengers capable of displaying both autocrine and paracrine activity. Whilst they are not as diverse as protein hormones or protein kinases, there are only five types of proteins. However, unlike protein kinases, there are no minor proteins among them; each follistatin-like protein performs an important physiological function. These proteins are involved in a variety of signaling pathways and biological processes, having the ability to bind to receptors such as DIP2A, TLR4, BMP and some others. The activation or experimentally induced knockout of the protein-coding genes often leads to fatal consequences for individual cells and the whole body as follistatin-like proteins indirectly regulate the cell cycle, tissue differentiation, metabolic pathways, and participate in the transmission chains of the pro-inflammatory intracellular signal. Abnormal course of these processes can cause the development of oncology or apoptosis, programmed cell death. There is still no comprehensive understanding of the spectrum of mechanisms of action of follistatin-like proteins, so the systematization and study of their cellular functions and regulation is an important direction of modern molecular and cell biology. Therefore, this review focuses on follistatin-related proteins that affect multiple targets and have direct or indirect effects on cellular signaling pathways, as well as to characterize the directions of their practical application in the field of biomedicine.

Keywords: biomarkers; cancer; cardiovascular disease; cellular signaling; follistatin-like proteins; inflammation; metabolism; respiratory disease.

Figure 2

Variety of follistatin-like proteins and their domain organization. SP: signal peptide; ND: N-terminal domain; FSD: Follistatin/Kazal-like domain; EF: a helix-loop-helix structural domain; VWFC: von Willebrand factor type C domain; IGFBP: IGF-binding domain; Ig: immunoglobulin-like domain; CD: C-terminal domain with acidic L-amino acids. The text on the right shows the accepted name of the protein and the number of its constituent amino acids (a.a.) [1,2,30,44,45,46,47].

Figure 3

Simplified diagram of the main signaling pathways characteristic of follistatin-like proteins (arrows imply activation of the pathway) [7,10,12,21,22,23,24,25,26,27,28,29,30,31,32,49].

Figure 1

(A) Follistatin-like proteins with high tissue-specific expression compared to follistatin (according to the HPA RNA-seq normal tissues project data annotated in the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/, accessed on 1 August 2021)) (RPKM—a normalized unit of transcript expression in reads per kilobase per million of mapped reads). (B) Follistatin-like proteins with medium or low tissue-specific expression compared to follistatin (according to the HPA RNA-seq normal tissues project data annotated in the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/, accessed on 1 August 2021)) (RPKM—a normalized unit of transcript expression in reads per kilobase per million of mapped reads).

Figure 1

(A) Follistatin-like proteins with high tissue-specific expression compared to follistatin (according to the HPA RNA-seq normal tissues project data annotated in the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/, accessed on 1 August 2021)) (RPKM—a normalized unit of transcript expression in reads per kilobase per million of mapped reads). (B) Follistatin-like proteins with medium or low tissue-specific expression compared to follistatin (according to the HPA RNA-seq normal tissues project data annotated in the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/, accessed on 1 August 2021)) (RPKM—a normalized unit of transcript expression in reads per kilobase per million of mapped reads).